Decline of programmed death-1-positive circulating T regulatory cells predicts more favourable clinical outcome of patients with melanoma under immune checkpoint blockade.

BACKGROUND: The role of T regulatory lymphocytes (Tregs) and their immunosuppressive mechanisms in the context of programmed death (PD)-1 blockade is not completely understood. OBJECTIVES: To assess the impact of PD-1-blocking antibody treatment on Treg subpopulations in the blood. METHODS: We studied circulating Treg subpopulations in patients with melanoma under nivolumab or pembrolizumab treatment using flow cytometry and correlated these findings with clinical outcomes. RESULTS: These analyses revealed that the frequency of CD4+  CD25++  CD127-  PD-1+ lymphocytes (PD-1+ Tregs) significantly decreased after the first cycle of immunotherapy (23% vs. 8·6%, P = 0·043). Compared with patients who did not show a significant decline of PD-1+ Tregs after the first treatment, those who did had better clinical outcomes with respect to progression-free survival (PFS, P = 0·022) and melanoma-specific death (MSD, P = 0·0038). Multivariate analysis confirmed that a significant decline of PD-1+ Tregs in peripheral blood after the first treatment cycle is a significant predictor of more favourable PFS and MSD (P = 0·04 and 0·017, respectively). Interestingly, the occurrence of immune-related adverse events was also an independent predictor for decreased risk of MSD (P = 0·047; odds ratio 0·064, 95% confidence interval 0·0042-0·97). CONCLUSIONS: We provide preliminary evidence that circulating PD-1+ Tregs rapidly decline after the initiation of treatment with PD-1-blocking antibodies, which is associated with reduced risk of melanoma progression and MSD. Patients showing no decrease of these PD-1+ Tregs in peripheral blood are characterized by an impaired response to immune checkpoint blockade and worse outcome. What's already known about this topic? Programmed death (PD)-1-blocking antibodies are highly effective in melanoma treatment. However, more than half of patients do not benefit from this therapy and to date it is difficult to predict which patients will respond to it. What does this study add? PD-1-blocking antibody therapy rapidly results in a decline of circulating PD-1+ T regulatory cells (Tregs). What is the translational message? Patients showing a decrease of PD-1+ Tregs appear to have better clinical outcome under PD-1 treatment.

Formation of antennal lobe and mushroom body neuropils during metamorphosis in the honeybee, apis mellifera.

The projections to the mushroom bodies (mbs) have been clearly described in the brain of adult honeybees (Apis mellifera). Olfactory projection neurons arborize in the lip of the calyceal neuropil, whereas visual projection neurons project to the collar. To study the maturation of this pattern of innervation, as well as the development of uniglomerular projection neurons within the antennal lobes (als), we conducted the following three studies focused on the first four stages of pupal development: mass staining of olfactory projection neurons, single cell labeling of olfactory projection neurons, and simultaneous labeling of olfactory projection neurons and visual projection neurons. Examination of whole-mount preparations with the confocal laser scanning microscope revealed that the olfactory projection neurons achieved their adult arborization pattern within their main output region, the lip of the mb calyces, earlier during development (pupal stage 1) than their dendritic processes within their main input region, the al (pupal stage 2). Simultaneous labeling experiments showed further that the fiber terminals of olfactory projection neurons and visual projection neurons did not overlap but instead occupied their respective projection areas within the mb calyces as early as pupal stage 1. We conclude that selective innervation of different subregions of the calycal neuropil precedes the segregation of glomerular units within the antennal lobe neuropil, and that the Kenyon cells themselves provide a template for the innervation of olfactory and visual projection neurons.

Delayed fetal development in two models of disturbed pregnancy of rats. Effect on mortality, body mass development, blood urea nitrogen (BUN) and urinary ammonium concentrations during the first week of extrauterine life.

To induce pregnancy disturbance, two models were used ("endotoxin-model" and "stress-model"), both causing decreased fetal body mass. Fetuses were delivered by Caesarean section in the morning of the 21st gestational day. Postnatal mortality rate during rearing for one week amounted to 12% in controls and was enhanced in the endotoxin- and stress-models (to approximately 25% and approximately 30%, respectively). During this period body mass gain of surviving pups was significantly delayed in the stress-model (approximately 140% of birth mass), compared with controls or pups of the endotoxin-model (160% and 155%, respectively). Additionally, decreased BUN concentrations were registered in newborns as well as 7-day-old pups of the stress-model. Urinary ammonium concentrations were not changed significantly. Possible alterations of metabolic processes in pups of the stress-model are discussed.

[Basic diagnostic program in dizziness and syncope symptoms: value of electrophysiologic studies of the heart]. / Diagnostisches Basisprogramm bei der Symptomatik Schwindel und Synkope: Stellenwert elektrophysiologischer Untersuchungen des Herzens.

Syncopes and preceding signs and symptoms, particularly also in form of appearances of giddiness, are, including specialists of various branches, among others ENT, neurology, orthopaedics and ophthalmology, always to be classified according to the fact whether or not a cardiovascular disease is to be regarded as cause. If there is the suspicion, both special non-invasive investigations and such ones which possibly are to be performed invasively are indicated. The latter come after the non-invasive investigations partly on account of the expenditure (technique of heart catheterization) and the possibilities of complication. The testing of the sinus node with the highly frequent atrial stimulation and single stimulus technique, the lead of the His-potential and the performance of a ventricular programmed stimulation are the fundamental programmes of an electrophysiologic investigation. In an analysis carried out more than 3 years could be found that in two thirds of the 45 invasively examined patients the diagnosis could be precised and enhanced, respectively, and that the main disturbances related to the signs and symptoms were a sick sinus syndrome, AV-asequences and ventricular arrhythmias.

[Results of a questionnaire survey of pulmonary complaints of dental technicians: effect of the duration of occupational activity (total exposure time)]. / Ergebnisse einer Fragebogenerhebung zu pulmonalen Beschwerden von Zahntechnikern: Einfluss der beruflichen Tätigkeitsdauer (Gesamt-Expositionszeit).

UNLABELLED: With the aid of a questionnaire survey conducted among 3,415 dental laboratories in Hesse and North Rhine Westphalia, the incidence of pulmonary symptoms among dental technicians, and their relationship to dust (exposure time: ET) was established. A total of 5,100 questionnaires were evaluable. The median age of the participants was 29 years, the ET 8 years. A total of 49.1% smoked cigarettes, 15.8% were ex-smokers, and 38% non-smokers. SYMPTOMS: 33.9% had unproductive cough, 25.4% experienced dyspnoea on effort, 18.9% had a productive cough, 5.7% episodic apnoea, 5.2% apnoea with audible wheezing, 3.6% apnoea at rest. In order to eliminate the "overlapping" influence of smoking habits, age and sex, in a matched-pair analysis, a comparison of short exposure time groups (SET: ET less than 5 years), and long exposure time groups (LET: ET greater than or equal to 5 years) was made for each symptom. The median ET for all SET was 3 (range: 0-4); for all LET 10 (range: 5-40) years. The frequency of the symptoms was generally greater in the LET group than in the sET group. Statistically significant differences were found for unproductive cough, productive cough, apnoea of effort, and episodic dyspnoea. No differences were found for apnoea at rest and dyspnoea with audible wheezing. Since such confounding factors as sex, age and smoking habits were excluded, our results point to a causal relationship between the pulmonary symptoms of dental technicians and occupational exposure to dust in the dental laboratory. These results are supported by the results of clinical and radiological study.

[Results of a questionnaire survey of pulmonary complaints in dental technicians: effect of inhalation exposure to heavy metal dusts (cobalt-chromium alloys)]. / Ergebnisse einer Fragebogenerhebung zu pulmonalen Beschwerden von Zahntechnikern: Einfluss der inhalativen Belastung durch Schwermetallstäube (Kobalt-Chrom-Legierungen).

In the course of their working lifetime, dental technicians are exposed to numerous different dusts, some of which also contain toxic substances (Co-Cr alloys), which are employed in the so-called model casting. In order to establish the influence of the nature of the exposure associated with various dental technical procedures on pulmonary symptoms, 24588 questionnaires were sent to 3415 dental laboratories. The return rate was 21.3%. An evaluation of 4328 questionnaires (with account being taken of the influence of smoking, age and sex), revealed a significant relationship between the duration of work on model casting, and the common symptoms "dry cough", "dyspnoea on exertion" and "productive cough". In agreement with other case reports, the results emphasize the significance of the inhalation of heavy metal dusts in the aetiology of pneumoconiosis in dental technicians.

[Effect of histamine H2 receptor blockers on hepatic elimination of drugs]. / Der Einfluss von Histamin-H2-Rezeptorenblocker auf die hepatische Elimination von Arzneimitteln.

In an investigation is proved that already after a treatment with the histamine-H2-receptor blocker Cimetidine (Altramet) lasting 14 days the elimination of Antipyrine is significantly delayed. In 14 male patients suffering from peptic ulcer the half-life period of Antipyrine (t50) was 8.6 +/- 0.6 h, whereas in the second test after 14 days it was 13 +/- 0.8 h. The systemic clearance (Cltot) was estimated with 78 +/- 11.3 ml X min-1 before treatment and with 40.8 +/- 3.6 ml X min-1 after treatment. It is pointed out that under a therapy with Cimetidine preparations and simultaneous application of medicaments which were eliminated by the so-called phase-I-reaction a hepatic interaction may occur.